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miR-26a and miR-384-5p are required for LTP maintenance and spine enlargement.

Gu QH, Yu D, Hu Z, Liu X, Yang Y, Luo Y, Zhu J, Li Z - Nat Commun (2015)

Bottom Line: Long-term potentiation (LTP) is a form of synaptic plasticity that results in enhanced synaptic strength.Using bioinformatics, we also examine the global effects of miRNA transcriptome changes during LTP on gene expression and cellular activities.This study reveals a novel miRNA-mediated mechanism for gene-specific regulation of translation in LTP, identifies two miRNAs required for long-lasting synaptic and spine plasticity and presents a catalogue of candidate 'LTP miRNAs'.

View Article: PubMed Central - PubMed

Affiliation: Unit on Synapse Development and Plasticity, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.

ABSTRACT
Long-term potentiation (LTP) is a form of synaptic plasticity that results in enhanced synaptic strength. It is associated with the formation and enlargement of dendritic spines-tiny protrusions accommodating excitatory synapses. Both LTP and spine remodelling are crucial for brain development, cognition and the pathophysiology of neurological disorders. The role of microRNAs (miRNAs) in the maintenance of LTP, however, is not well understood. Using next-generation sequencing to profile miRNA transcriptomes, we demonstrate that miR-26a and miR-384-5p specifically affect the maintenance, but not induction, of LTP and different stages of spine enlargement by regulating the expression of RSK3. Using bioinformatics, we also examine the global effects of miRNA transcriptome changes during LTP on gene expression and cellular activities. This study reveals a novel miRNA-mediated mechanism for gene-specific regulation of translation in LTP, identifies two miRNAs required for long-lasting synaptic and spine plasticity and presents a catalogue of candidate 'LTP miRNAs'.

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RSK3 mediates the effect of miR-26a on spine plasticity.(a) Representative images. (b–i) Quantification of spine area and spine density. For BI-D1870 treatment, BI-D1870 was added to the medium at 5 min before TEA treatment. n=13–16 neurons for each condition. Data are presented as mean±s.e.m. Kruskal–Wallis and Mann–Whitney U-tests are used for statistical analysis. *P<0.05, **P<0.01, ***P<0.001. Scale bar, 20 μm for low-magnification images and 5 μm for high-magnification images.
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f6: RSK3 mediates the effect of miR-26a on spine plasticity.(a) Representative images. (b–i) Quantification of spine area and spine density. For BI-D1870 treatment, BI-D1870 was added to the medium at 5 min before TEA treatment. n=13–16 neurons for each condition. Data are presented as mean±s.e.m. Kruskal–Wallis and Mann–Whitney U-tests are used for statistical analysis. *P<0.05, **P<0.01, ***P<0.001. Scale bar, 20 μm for low-magnification images and 5 μm for high-magnification images.

Mentions: Having found that miR-26a and miR-384-5p both target RSK3 to regulate LTP, we next tested whether they also target RSK3 for spine remodelling. First, we tested whether RSK3 is involved in spine plasticity. We transfected cultured hippocampal neurons (DIV14) with the RSK3 siRNA construct, and treated them with TEA (25 mM, 15 min) at 2∼3 days after transfection. Transfection of the RSK3 siRNA construct obliterated TEA-induced spine enlargement at 90 min, but not at 10 min post stimulation (Fig. 6a,b). TEA-induced spine formation was also blocked by transfection of the RSK3 siRNA construct (Fig. 6a,f). The blockade of TEA-induced spine formation and enlargement by RSK3 siRNA, however, was inhibited by co-transfection with a construct expressing siRNA-resistant RSK3, confirming that the effects of RSK siRNA are specific (Fig. 6a,b,f). Likewise, BI-D1870 treatment abolished TEA-induced spine formation and long-lasting spine enlargement (Fig. 6a,c,g). These results indicate that RSK3 is required for spine formation and for the maintenance (but not the induction) of spine enlargement induced by TEA treatment.


miR-26a and miR-384-5p are required for LTP maintenance and spine enlargement.

Gu QH, Yu D, Hu Z, Liu X, Yang Y, Luo Y, Zhu J, Li Z - Nat Commun (2015)

RSK3 mediates the effect of miR-26a on spine plasticity.(a) Representative images. (b–i) Quantification of spine area and spine density. For BI-D1870 treatment, BI-D1870 was added to the medium at 5 min before TEA treatment. n=13–16 neurons for each condition. Data are presented as mean±s.e.m. Kruskal–Wallis and Mann–Whitney U-tests are used for statistical analysis. *P<0.05, **P<0.01, ***P<0.001. Scale bar, 20 μm for low-magnification images and 5 μm for high-magnification images.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403380&req=5

f6: RSK3 mediates the effect of miR-26a on spine plasticity.(a) Representative images. (b–i) Quantification of spine area and spine density. For BI-D1870 treatment, BI-D1870 was added to the medium at 5 min before TEA treatment. n=13–16 neurons for each condition. Data are presented as mean±s.e.m. Kruskal–Wallis and Mann–Whitney U-tests are used for statistical analysis. *P<0.05, **P<0.01, ***P<0.001. Scale bar, 20 μm for low-magnification images and 5 μm for high-magnification images.
Mentions: Having found that miR-26a and miR-384-5p both target RSK3 to regulate LTP, we next tested whether they also target RSK3 for spine remodelling. First, we tested whether RSK3 is involved in spine plasticity. We transfected cultured hippocampal neurons (DIV14) with the RSK3 siRNA construct, and treated them with TEA (25 mM, 15 min) at 2∼3 days after transfection. Transfection of the RSK3 siRNA construct obliterated TEA-induced spine enlargement at 90 min, but not at 10 min post stimulation (Fig. 6a,b). TEA-induced spine formation was also blocked by transfection of the RSK3 siRNA construct (Fig. 6a,f). The blockade of TEA-induced spine formation and enlargement by RSK3 siRNA, however, was inhibited by co-transfection with a construct expressing siRNA-resistant RSK3, confirming that the effects of RSK siRNA are specific (Fig. 6a,b,f). Likewise, BI-D1870 treatment abolished TEA-induced spine formation and long-lasting spine enlargement (Fig. 6a,c,g). These results indicate that RSK3 is required for spine formation and for the maintenance (but not the induction) of spine enlargement induced by TEA treatment.

Bottom Line: Long-term potentiation (LTP) is a form of synaptic plasticity that results in enhanced synaptic strength.Using bioinformatics, we also examine the global effects of miRNA transcriptome changes during LTP on gene expression and cellular activities.This study reveals a novel miRNA-mediated mechanism for gene-specific regulation of translation in LTP, identifies two miRNAs required for long-lasting synaptic and spine plasticity and presents a catalogue of candidate 'LTP miRNAs'.

View Article: PubMed Central - PubMed

Affiliation: Unit on Synapse Development and Plasticity, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.

ABSTRACT
Long-term potentiation (LTP) is a form of synaptic plasticity that results in enhanced synaptic strength. It is associated with the formation and enlargement of dendritic spines-tiny protrusions accommodating excitatory synapses. Both LTP and spine remodelling are crucial for brain development, cognition and the pathophysiology of neurological disorders. The role of microRNAs (miRNAs) in the maintenance of LTP, however, is not well understood. Using next-generation sequencing to profile miRNA transcriptomes, we demonstrate that miR-26a and miR-384-5p specifically affect the maintenance, but not induction, of LTP and different stages of spine enlargement by regulating the expression of RSK3. Using bioinformatics, we also examine the global effects of miRNA transcriptome changes during LTP on gene expression and cellular activities. This study reveals a novel miRNA-mediated mechanism for gene-specific regulation of translation in LTP, identifies two miRNAs required for long-lasting synaptic and spine plasticity and presents a catalogue of candidate 'LTP miRNAs'.

Show MeSH
Related in: MedlinePlus